Inflammatory bowel diseases
Smad7, a negative regulator of TGF-β signaling, has been implicated in the pathogenesis and treatment of inflammatory bowel diseases (IBDs), such as Crohn’s disease (CD) and ulcerative colitis (UC). However, the molecular mechanisms underlying Smad7 pathogenic functions in IBDs remain poorly understood. Here, we uncovered a novel role for Smad7 in mediating intestinal inflammation by limiting the PDL2/1-PD1 axis in dendritic cells (DCs) and CD4+ T cells. Smad7 deficiency in DCs promotes TGF-β responsiveness and expression of the co-inhibitory molecules PDL2/1 on DCs, and further imprints T cell-PD1 signaling to promote Treg differentiation. DC-specific Smad7 deletion mitigates DSS-induced colitis in mice and is mediated by increased CD103+ PDL2/1+ DCs and Tregs. Additionally, Smad7 deficiency in CD4+ T cells promotes PD1 expression and PD1-mediated Treg differentiation in vitro. Adoptive transfer of Smad7-deficient CD4+ T cells enhances Treg development in vivo and confers striking protection against a T cell-mediated colitis model. Furthermore, antisense Smad7 oligonucleotide treatment ameliorates DSS-induced UC and increases TGF-β and PDL2/1-PD1 signaling. Together,our results identify previously unknown mechanisms by which Smad7 mediates intestinal inflammation and leverages these pathways therapeutically, providing novel strategies for IBD intervention.